Ovarian neuromodulation and associated systems and methods

ABSTRACT

Methods for treating polycystic ovary syndrome with therapeutic ovarian neuromodulation and associated systems and methods are disclosed herein. Polycystic ovary syndrome can be associated, for example, with a condition including at least one of oligo/amenorrhea, infertility, hirsutism, obesity, metabolic syndrome, insulin resistance, and increased cardiovascular risk profile. One aspect of the present technology is directed to methods that at least partially inhibit sympathetic neural activity in nerves proximate an ovarian artery of an ovary of a patient. Sympathetic drive in the patient can thereby be reduced in a manner that treats the patient for the polycystic ovary syndrome. Ovarian sympathetic nerve activity can be modulated along afferent and/or efferent pathways. The modulation can be achieved, for example, using an intravascularly positioned catheter carrying a therapeutic assembly, e.g., a therapeutic assembly configured to use electrically-induced, thermally-induced, and/or chemically-induced approaches to modulate the ovarian nerve.

CROSS-REFERENCE TO RELATED APPLICATION(S)

The present application is a Continuation of and claims priority to U.S.patent application Ser. No. 14/379,890, filed Aug. 20, 2014, now U.S.Pat. No. 9,750,568, which is a U.S. National Phase under 35 U.S.C. 371of International Application No. PCT/US2013/29690, filed Mar. 7, 2013,which claims priority to U.S. Provisional Patent Application No.61/608,452, filed Mar. 8, 2012, the disclosures of which areincorporated herein in their entirety by reference.

TECHNICAL FIELD

The present technology relates generally to modulation of ovarian nervesand associated systems and methods.

BACKGROUND

Ovarian sympathetic neural activity can cause or exacerbate severalovarian conditions, including, but not limited to, polycystic ovarysyndrome, infertility, and dysfunctional hormone or steroid production.Polycystic ovary syndrome (PCOS) is a common endocrine disorderaffecting women of reproductive ages (e.g., 12-45 years old). Symptomsof PCOS can include oligoovulation or anovulation resulting in irregularmenstruation, amenorrhea, ovulation-related infertility, and enlarged orpolycystic ovaries. Other symptoms include excess of androgenic hormones(e.g., testosterone) which can result in acne and hirsutism. Clinicalcomplications, such as insulin resistance, obesity, Type 2 diabetes,high cholesterol, and hypertension can also be common in PCOS patients.Further complications can include development of endometrial cancer orbreast cancer. Most prescribed treatments address specificmanifestations of PCOS and do not address underlying causes of thedisease. Moreover, many of these treatments only address specificsequelae (e.g., individual symptoms or indications) of the disease, andpatients can be required to combine multiple treatment programs fortreating these conditions and/or complications separately. For example,androgen excess and associated symptoms (e.g., hirsutism, acne) arecommonly treated with estrogen-progestin contraceptives, antiandrogens,anti-acne treatments, and prescription drugs and over-the-counterdepilatories for removing or slowing unwanted hair growth. Additionally,anovulation and fertility issues are treated with ovulation promotingdrugs (e.g., clomiphene or follicle stimulating hormone (FSH)injections) or in vitro fertilization. Other treatments are prescribedfor PCOS patients having hypertension (e.g., anti-hypertensivemedications), hyperlipidemia (e.g., statins, other cholesterol loweringagents), and insulin resistance/Type 2 diabetes (e.g., metformin, otherdiabetic medications). Such pharmacologic strategies, however, havesignificant limitations including limited efficacy, side effects,long-term maintenance regimens and others.

The sympathetic nervous system (SNS) is a primarily involuntary bodilycontrol system typically associated with stress responses. Fibers of theSNS extend through tissue in almost every organ system of the humanbody. For example, some fibers extend from the brain, intertwine alongthe aorta, and branch out to various organs. As groups of fibersapproach specific organs, fibers particular to the organs can separatefrom the groups. Signals sent via these and other fibers can affectcharacteristics such as pupil diameter, gut motility, and urinaryoutput. Such regulation can have adaptive utility in maintaininghomeostasis or in preparing the body for rapid response to environmentalfactors. Chronic activation of the SNS, however, is a common maladaptiveresponse that can drive the progression of many disease states.Excessive activation of the ovarian SNS has been identifiedexperimentally and in humans as a likely contributor to the complexpathophysiology of PCOS. As examples, studies measuring efferentpostganglionic muscle sympathetic nerve activity (MSNA) in PCOS patientsrevealed that PCOS is associated with high MSNA. Elevated testosteroneand cholesterol lipid levels were identified as independent predictorsof MSNA in PCOS. Involvement of the SNS in PCOS can be furthercharacterized by finding that there is a greater density ofcatecholaminergic nerve fibers in polycystic ovaries and alteredperipheral catecholamine secretion in adolescent PCOS patients. It isalso known that activation of the sympathetic neurons innervating theovary precedes the development of cystic ovaries in rats.

BRIEF DESCRIPTION OF THE DRAWINGS

Many aspects of the present disclosure can be better understood withreference to the following drawings. The components in the drawings arenot necessarily to scale. Instead, emphasis is placed on illustratingclearly the principles of the present disclosure.

FIG. 1A is an anatomical view illustrating the ovarian artery and nearbyorgans and vessels.

FIG. 1B is a partially cross-sectional view illustrating neuromodulationat a treatment location within the ovarian artery in accordance with anembodiment of the present technology.

FIGS. 2A and 2B are anatomic views of the arterial vasculature andvenous vasculature, respectively, of a human.

FIG. 3 illustrates an intravascular neuromodulation system configured inaccordance with an embodiment of the present technology.

FIG. 4 is a block diagram illustrating a method of modulating ovariannerves in accordance with an embodiment of the present technology.

FIG. 5 is a conceptual illustration of the SNS and how the braincommunicates with the body via the SNS.

FIG. 6 is an enlarged anatomic view of arterial vasculature and anatomyof a left ovary.

FIG. 7A is a plot of systolic office blood pressure (mmHg) at a baselineassessment and at 12 weeks after renal neuromodulation for two patientswith polycystic ovary syndrome (PCOS).

FIG. 7B is a plot of muscle sympathetic nerve activity (bursts per 100heart beats) at a baseline assessment and at 12 weeks after renalneuromodulation for two patients with PCOS.

FIG. 7C is a plot of whole body norepinephrine spillover (ng/min) at abaseline assessment and at 12 weeks after renal neuromodulation for twopatients with PCOS.

FIG. 8A is a plot of body weight (kg) at a baseline assessment and at 12weeks after renal neuromodulation for two patients with PCOS.

FIG. 8B is a plot of fasting plasma glucose (mmol/l) at a baselineassessment and at 12 weeks after renal neuromodulation for two patientswith PCOS.

FIG. 8C is a plot of insulin sensitivity (mg/kg per min) at a baselineassessment and at 12 weeks after renal neuromodulation for two patientswith PCOS.

FIG. 8D is a plot of cystatin C (mg/l) at a baseline assessment and at12 weeks after renal neuromodulation for two patients with PCOS.

FIG. 8E is a plot of creatinine clearance (ml/min) at a baselineassessment and at 12 weeks after renal neuromodulation for two patientswith PCOS.

FIG. 8F is a plot of urinary albumin creatinine ratio (mg/g creatinine)at a baseline assessment and at 12 weeks after renal neuromodulation fortwo patients with PCOS.

DETAILED DESCRIPTION

The present technology is generally directed to modulation of ovariannerves to treat at least one condition associated with ovariansympathetic activity (e.g., overactivity or hyperactivity) and/orcentral sympathetic activity (e.g., overactivity or hyperactivity). Forexample, several embodiments are directed to modulation of ovariannerves to treat polycystic ovary syndrome and related conditions, suchas infertility and dysfunctional hormone or steroid production. Asdiscussed in greater detail below, ovarian neuromodulation can includerendering neural fibers inert, inactive, or otherwise completely orpartially reduced in function. This result can be electrically-induced,thermally-induced, or induced by another mechanism during an ovarianneuromodulation procedure, e.g., a procedure including percutaneoustransluminal intravascular access.

Specific details of several embodiments of the technology are describedbelow with reference to FIGS. 1A-8F. The embodiments can include, forexample, modulating nerves proximate (e.g., at or near) an ovarianartery, an ovarian vein, and/or other suitable structures. Although manyof the embodiments are described herein with respect toelectrically-induced, thermally-induced, and chemically-inducedapproaches, other treatment modalities in addition to those describedherein are within the scope of the present technology. Additionally,other embodiments of the present technology can have differentconfigurations, components, or procedures than those described herein. Aperson of ordinary skill in the art, therefore, will accordinglyunderstand that the technology can have other embodiments withadditional elements and that the technology can have other embodimentswithout several of the features shown and described below with referenceto FIGS. 1A-8F.

As used herein, the terms “distal” and “proximal” define a position ordirection with respect to the treating clinician or clinician's controldevice (e.g., a handle assembly). “Distal” or “distally” can refer to aposition distant from or in a direction away from the clinician orclinician's control device. “Proximal” and “proximally” can refer to aposition near or in a direction toward the clinician or clinician'scontrol device.

I. POLYCYSTIC OVARY SYNDROME

PCOS is a common endocrine abnormality in women and can be characterizedby androgen excess, hyperinsulinemia, and/or other physiologicalconditions. The etiology of PCOS is uncertain; however evidence suggeststhat it results from both genetic susceptibility as well asenvironmental influences including the presence of obesity. The clinicalpresentation of PCOS can include reproductive (e.g., oligo/amenorrhea,infertility, and hirsutism), metabolic (e.g., obesity, metabolicsyndrome, insulin resistance, increased cardiovascular risk profile),and psychological (e.g., depression, anxiety, body dissatisfaction andeating disorders, diminished sexual satisfaction, etc.) features.Experimentally, PCOS has been shown to correlate with a localizedincrease in ovarian sympathetic nerve activity (Lara et al., 1993,Endocrinology 133: 2690-2695; incorporated herein by reference in itsentirety) and global increase in sympathetic nervous system tone such asMSNA (Sverrisdottir et al., 2008, Am J Physiol Endocrinol Metab 294:E576-581; incorporated herein by reference in its entirety).Additionally, the degree of sympathoexcitation may be related to thedegree of PCOS severity.

Sympathetic nerves can contribute to cardiovascular, metabolic, and/orother features that characterize PCOS. For example, among other PCOSpresentations, obesity and hypertension can be characterized byincreased efferent sympathetic drive to the kidneys and increasedsystemic sympathetic nerve firing modulated by afferent signaling fromrenal sensory nerves. The role of renal sympathetic nerves ascontributors to the pathogenesis of elevated blood pressure,particularly in obese patients, has been demonstrated bothexperimentally and in humans. Apart from its role in cardiovascularregulation, sympathetic nervous system activation also has metaboliceffects resulting in increased lipolysis and increased levels of fattyacids in plasma, increased hepatic gluconeogenesis, and alterations inpancreatic insulin release. Chronic sympathetic activation predisposesto the development of insulin resistance, which is often associated withobesity and hypertension and can be a key feature of PCOS.

A patient suspected of having PCOS can be positively diagnosed if theypresent with the following criteria: (1) excess androgen activity, (2)oligoovulation/anovulation and/or polycystic ovaries (assessed, forexample, by gynecologic ultrasound or pelvic laparoscopy), and (3) otherentities are excluded that would cause excess androgen activity.Androgen excess can be tested by measuring total and free testosteronelevels. Androstenedione (an androgen precursor) can also be measured aslevels are typically elevated in female patients having PCOS. Asexamples, polycystic ovaries can be substantiated by a finding of twelveor more follicles measuring 2-9 mm in diameter, or by finding increasedovarian volume (>10 cm³). Further tests for imbalances and/orirregularities in patients suspected of having or having been diagnosedwith PCOS using the above criteria can include assessing levels ofhormones (e.g., estrogen, FSH, LH, 17-ketosteriods), fasting glucoselevels, lipid levels, prolactin levels, and thyroid function tests. Infurther embodiments, PCOS patients or patients suspected of having PCOScan be assessed for elevated sympathetic nerve activity, includingestablishing measurements for markers of elevated sympathetic nerveactivity, including for example, MSNA, total body plasma norepinephrinespillover levels, and heart rate variability.

II. OVARIAN NEUROMODULATION

Ovarian neuromodulation is the partial or complete incapacitation orother effective disruption or regulation of nerves innervating theovaries, e.g., nerves terminating in or originating from an ovary or instructures closely associated with an ovary. In particular, ovarianneuromodulation comprises inhibiting, reducing, blocking, pacing,upregulating, and/or downregulating neural communication along neuralfibers (e.g., efferent and/or afferent neural fibers) innervating theovaries. Such incapacitation, disruption, and/or regulation can belong-term (e.g., permanent or for periods of months, years, or decades)or short-term (e.g., for periods of minutes, hours, days, or weeks).While long-term disruption of the ovarian nerves can be desirable foralleviating symptoms and other sequelae associated with PCOS over longerperiods of time, short-term modulation of the ovarian nerves may also bedesirable. For example, some patients may benefit from short-termmodulation to address issues relating to fertility (e.g., to induceovulation). Ovarian sympathetic neural activity can cause or exacerbateseveral ovarian conditions, including, but not limited to, polycysticovary syndrome, infertility, and dysfunctional hormone or steroidproduction. Ovarian neuromodulation is expected to be useful in treatingthese conditions. Methods and systems for ovarian neuromodulation forefficaciously treating several clinical conditions characterized byincreased ovarian sympathetic activity, such as PCOS and associatedconditions, are described herein.

Furthermore, ovarian afferent sympathetic activity can contribute tocentral sympathetic tone or drive. Accordingly, ovarian neuromodulationis expected to be useful in treating clinical conditions associated withcentral sympathetic activity (e.g., overactivity or hyperactivity),particularly conditions associated with central sympatheticoverstimulation. Conditions associated with central sympathetic activity(e.g., overactivity or hyperactivity) include, for example,hypertension, heart failure, acute myocardial infarction, metabolicsyndrome, insulin resistance, diabetes, left ventricular hypertrophy,chronic and end stage renal disease, inappropriate fluid retention inheart failure, cardio-renal syndrome, polycystic kidney disease,osteoporosis, and sudden death, among other conditions.

By way of theory, targeting both afferent and efferent ovarian nerves(e.g., via a catheter-based approach, extracorporeal ultrasound) maycause beneficial effects extending well beyond the ovaries and othersystemic sequelae of PCOS, such as increased cardiovascular risk. Therole of sympathetic activation for blood pressure regulation is wellestablished, as is the relevance of increased renal sympathetic nerveactivity for the alterations in renal blood flow and glomerularfiltration rate. There is now also clear evidence that sympatheticactivation results in adverse consequences on metabolic control,including insulin sensitivity. Additionally, overactivity of thesympathetic nervous system is implicated in the specific etiology ofPCOS. Some aspects of methods of treating PCOS patients using ovarianneuromodulation are at least in part derived from the recognitiondescribed herein that the ovaries may contribute to elevated centralsympathetic drive.

While the ovarian nerves function to innervate the ovaries and connectthe ovaries with the central nervous system, the ovarian nerves may beunnecessary for general health. Accordingly, in some patients, such aspatients having PCOS, reducing ovarian sympathetic drive, centralsympathetic drive, and/or achieving other benefits obtained from ovarianneuromodulation can outweigh the complete or partial loss ofovarian-nerve functionality.

Several properties of the ovarian vasculature may inform the design oftreatment devices and associated methods for achieving ovarianneuromodulation, for example, via intravascular access, and imposespecific design requirements for such devices. Specific designrequirements may include accessing the ovarian artery, facilitatingstable contact between the energy delivery elements of such devices anda luminal surface or wall of the ovarian artery, and/or effectivelymodulating the ovarian nerves with the neuromodulatory apparatus.

A. Selected Examples of Neuromodulation Modalities

Various techniques can be used to partially or completely incapacitateneural pathways, such as those innervating the ovary. Ovarianneuromodulation in accordance with embodiments of the present technologycan be electrically-induced, thermally-induced, chemically-induced, orinduced in another suitable manner or combination of manners at one ormore suitable treatment locations during a treatment procedure. Forexample, the purposeful application of radio frequency (RF) energy(monopolar and/or bipolar), pulsed RF energy, microwave energy, opticalenergy, ultrasound energy (e.g., intravascularly delivered ultrasound,extracorporeal ultrasound, high-intensity focused ultrasound (HIFU)),cryotherapeutic energy, direct heat energy, radiation (e.g., infrared,visible, gamma), chemicals (e.g., drugs or other agents), orcombinations thereof to tissue at a treatment location can induce one ormore desired effects at the treatment location, e.g., broadly across thetreatment location or at localized regions of the treatment location.

FIG. 1A is an anatomical view illustrating the ovaries 10 and nearbyorgans and vessels, including an ovarian artery 12. Treatment proceduresfor ovarian neuromodulation in accordance with embodiments of thepresent technology can include applying a treatment modality at one ormore treatment locations proximate a structure having a relatively highconcentration of ovarian nerves. In some embodiments, for example, atleast one treatment location can be proximate a portion of the ovarianartery 12, a branch of the ovarian artery 12, an ostium of the ovarianartery 12, an ovarian vein 14, a branch of an ovarian vein, an ostium ofan ovarian vein, and/or another suitable structure (e.g., anothersuitable structure extending along the suspensory ligament) in thevicinity of ovarian nerves. FIG. 1B, for example, is a cross-sectionalview illustrating neuromodulation at a treatment location within theovarian artery 12. As shown in FIG. 1B, a treatment device 16 includinga shaft 18 and a therapeutic element 20 can be extended toward theovarian artery 12 to locate the therapeutic element 20 at the treatmentlocation within the ovarian artery 12. The therapeutic element 20 can beconfigured for neuromodulation at the treatment location via a suitabletreatment modality, e.g., cryotherapeutic, direct heat, electrode-based,transducer-based, chemical-based, or another suitable treatmentmodality.

The treatment location can be proximate (e.g., at or near) a vessel orchamber wall (e.g., a wall of an ovarian artery, an ovarian vein, and/oranother suitable structure), and the treated tissue can include tissueproximate the treatment location. For example, with regard to theovarian artery 12, a treatment procedure can include modulating nervesin the ovarian plexus, which lay at least partially within or adjacentto the adventitia of the ovarian artery. In some embodiments it may bedesirable to modulate ovarian nerves from a treatment location within avessel and in close proximity to an ovary, e.g., closer to the ovary 10than to a trunk of the vessel. This can increase the likelihood ofmodulating nerves specific to the ovary, while decreasing the likelihoodof modulating nerves that extend to other organs. Vessels can decreasein diameter and become more tortuous as they extend toward an ovary 10.Accordingly, modulating ovarian nerves from a treatment location inclose proximity to an ovary can include using a device (e.g., treatmentdevice 16) having size, flexibility, torque-ability, kink resistance,and/or other characteristics suitable for accessing narrow and/ortortuous portions of vessels.

In some embodiments, the purposeful application of energy (e.g.,electrical energy, thermal energy, etc.) to tissue can induce one ormore desired thermal heating and/or cooling effects on localized regionsof the ovarian artery 12, for example, and adjacent regions along all ora portion of the ovarian plexus, which lay intimately within or adjacentto the adventitia of the ovarian artery (e.g., carried in the suspensoryligament of the ovary). Some embodiments of the present technology, forexample, include cryotherapeutic ovarian neuromodulation, which caninclude cooling tissue at a target site in a manner that modulatesneural function. The mechanisms of cryotherapeutic tissue damageinclude, for example, direct cell injury (e.g., necrosis), vascularinjury (e.g., starving the cell from nutrients by damaging supplyingblood vessels), and sublethal hypothermia with subsequent apoptosis.Exposure to cryotherapeutic cooling can cause acute cell death (e.g.,immediately after exposure) and/or delayed cell death (e.g., duringtissue thawing and subsequent hyperperfusion). Several embodiments ofthe present technology include cooling a structure at or near an innersurface of a vessel or chamber wall such that proximate (e.g., adjacent)tissue is effectively cooled to a depth where sympathetic (efferentand/or afferent) ovarian nerves reside. For example, a cooling structurecan be cooled to the extent that it causes therapeutically-effective,cryogenic ovarian-nerve modulation. Sufficiently cooling at least aportion of a sympathetic ovarian nerve may slow or potentially blockconduction of neural signals to produce a prolonged or permanentreduction in ovarian sympathetic activity. In some embodiments, acryotherapeutic treatment modality can include cooling that is notconfigured to cause neuromodulation. For example, the cooling can be ator above cryogenic temperatures and can be used to controlneuromodulation via another treatment modality, e.g., to reduce damageto non-targeted tissue when targeted tissue adjacent to the non-targetedtissue is heated.

Cryotherapeutic treatment can be beneficial in certain embodiments. Forexample, rapidly cooling tissue can provide an analgesic effect suchthat cryotherapeutic treatment can be less painful than other treatmentmodalities. Neuromodulation using cryotherapeutic treatment cantherefore require less analgesic medication to maintain patient comfortduring a treatment procedure compared to neuromodulation using othertreatment modalities. Additionally, reducing pain can reduce patientmovement and thereby increase operator success and/or reduce proceduralcomplications. Cryogenic cooling also typically does not causesignificant collagen tightening, and therefore is not typicallyassociated with vessel stenosis. In some embodiments, cryotherapeutictreatment can include cooling at temperatures that can cause therapeuticelements to adhere to moist tissue. This can be beneficial because itcan promote stable, consistent, and continued contact during treatment.The typical conditions of treatment can make this an attractive featurebecause, for example, patients can move during treatment, cathetersassociated with therapeutic elements can move, and/or respiration cancause the ovaries to rise and fall and thereby move the ovarianvasculature. In addition, blood flow is pulsatile and can causestructures associated with the ovaries to pulse. Cryogenic adhesion alsocan facilitate intravascular positioning, particularly in relativelysmall structures (e.g., relatively short arteries) in which stableintravascular positioning can be difficult to achieve.

As an alternative to or in conjunction with cryotherapeutic cooling,other suitable energy delivery techniques, such as electrode-based ortransducer-based approaches, can be used for therapeutically-effectiveovarian neuromodulation. Electrode-based or transducer-based treatmentcan include delivering electrical energy and/or another form of energyto tissue and/or heating tissue at a treatment location in a manner thatmodulates neural function. For example, sufficiently stimulating and/orheating at least a portion of a sympathetic ovarian nerve can slow orpotentially block conduction of neural signals to produce a prolonged orpermanent reduction in sympathetic activity. As noted previously,suitable energy modalities can include, for example, RF energy(monopolar and/or bipolar), pulsed RF energy, microwave energy,ultrasound energy (e.g., intravascularly delivered ultrasound,extracorporeal ultrasound, HIFU), laser energy, optical energy, magneticenergy, direct heat, or other suitable energy modalities alone or incombination. Where a system uses a monopolar configuration, a returnelectrode or ground patch fixed externally on the subject can be used.Moreover, electrodes (or other energy delivery elements) can be usedalone or with other electrodes in a multi-electrode array. Examples ofsuitable multi-electrode devices are described in U.S. patentapplication Ser. No. 13/281,360, filed Oct. 25, 2011, and incorporatedherein by reference in its entirety. Other suitable devices andtechnologies, such as cryotherapeutic devices, are described in U.S.patent application Ser. No. 13/279,330, filed Oct. 23, 2011, andadditional thermal devices are described in U.S. patent application Ser.No. 13/279,205, filed Oct. 21, 2011, each of which are incorporatedherein by reference in their entireties.

Thermal effects can include both thermal ablation and non-ablativethermal alteration or damage (e.g., via sustained heating and/orresistive heating) to partially or completely disrupt the ability of anerve to transmit a signal. Desired thermal heating effects, forexample, may include raising the temperature of target neural fibersabove a desired threshold to achieve non-ablative thermal alteration, orabove a higher temperature to achieve ablative thermal alteration. Forexample, the target temperature can be above body temperature (e.g.,approximately 37° C.) but less than about 45° C. for non-ablativethermal alteration, or the target temperature can be about 45° C. orhigher for ablative thermal alteration. More specifically, exposure tothermal energy in excess of a body temperature of about 37° C., butbelow a temperature of about 45° C., may induce thermal alteration viamoderate heating of target neural fibers or of vascular structures thatperfuse the target fibers. In cases where vascular structures areaffected, the target neural fibers may be denied perfusion resulting innecrosis of the neural tissue. For example, this may induce non-ablativethermal alteration in the fibers or structures. Exposure to heat above atemperature of about 45° C., or above about 60° C., may induce thermalalteration via substantial heating of the fibers or structures. Forexample, such higher temperatures may thermally ablate the target neuralfibers or the vascular structures that perfuse the target fibers. Insome patients, it may be desirable to achieve temperatures thatthermally ablate the target neural fibers or the vascular structures,but that are less than about 90° C., or less than about 85° C., or lessthan about 80° C., and/or less than about 75° C. Other embodiments caninclude heating tissue to a variety of other suitable temperatures.

In some embodiments, ovarian neuromodulation can include achemical-based treatment modality alone or in combination with anothertreatment modality. Neuromodulation using chemical-based treatment caninclude delivering one or more chemicals (e.g., drugs or other agents)to tissue at a treatment location in a manner that modulates neuralfunction. The chemical, for example, can be selected to affect thetreatment location generally or to selectively affect some structures atthe treatment location over other structures. For example, the chemicalcan be guanethidine, ethanol, phenol, vincristine, a neurotoxin, oranother suitable agent selected to alter, damage, or disrupt nerves. Insome embodiments, energy (e.g., light, ultrasound, or another suitabletype of energy) can be used to activate the chemical and/or to cause thechemical to become more bioavailable. A variety of suitable techniquescan be used to deliver chemicals to tissue at a treatment location. Forexample, chemicals can be delivered via one or more devices, such asneedles originating outside the body or within the vasculature ordelivery pumps (see, e.g., U.S. Pat. No. 6,978,174, the disclosure ofwhich is hereby incorporated by reference in its entirety). In anintravascular example, a catheter can be used to intravascularlyposition a therapeutic element including a plurality of needles (e.g.,micro-needles) that can be retracted or otherwise blocked prior todeployment. In other embodiments, a chemical can be introduced intotissue at a treatment location via simple diffusion through a vesselwall, electrophoresis, or another suitable mechanism. Similar techniquescan be used to introduce chemicals that are not configured to causeneuromodulation, but rather to facilitate neuromodulation via anothertreatment modality. Examples of such chemicals include, but are notlimited to, anesthetic agents and contrast agents.

In some embodiments, a treatment procedure can include applying asuitable treatment modality at a treatment location in a testing stepfollowed by a treatment step. The testing step, for example, can includeapplying the treatment modality at a lower intensity and/or for ashorter duration than during the treatment step. This can allow anoperator to determine (e.g., by neural activity sensors and/or patientfeedback) whether nerves proximate the treatment location are suitablefor modulation. Performing a testing step can be particularly useful fortreatment procedures in which targeted nerves are closely associatedwith nerves that could cause undesirable side effects if modulatedduring a subsequent treatment step.

B. Achieving Intravascular Access to the Ovarian Artery

In accordance with the present technology, neuromodulation of a leftand/or right ovarian nerve (e.g., ovarian plexus), which is intimatelyassociated with a left and/or right ovarian artery 12 (FIG. 1A), may beachieved through intravascular access. As FIG. 2A shows, blood moved bycontractions of the heart is conveyed from the left ventricle of theheart by the aorta. The aorta descends through the thorax and bifurcatesat the left and right iliac arteries. The left and right iliac arteriesdescend, respectively, through the left and right legs and join the leftand right femoral arteries.

As FIG. 2B shows, the blood collects in veins and returns to the heart,through the femoral veins into the iliac veins and into the inferiorvena cava. Above the renal veins, the inferior vena cava ascends toconvey blood into the right atrium of the heart. From the right atrium,the blood is pumped through the right ventricle into the lungs, where itis oxygenated. From the lungs, the oxygenated blood is conveyed into theleft atrium. From the left atrium, the oxygenated blood is conveyed bythe left ventricle back to the aorta.

As will be described in greater detail later, the femoral artery may beaccessed and cannulated at the base of the femoral triangle justinferior to the midpoint of the inguinal ligament. A catheter (notshown) may be inserted percutaneously into the femoral artery throughthis access site, passed through the iliac artery and aorta, and placedinto either the left or right ovarian artery 12 (FIG. 1A). This routecomprises an intravascular path that offers minimally invasive access toa respective ovarian artery 12 and/or other ovarian blood vessels.

Another location for introduction of a catheter in the arterial systemis through the femoral artery (as described above), passed through tothe internal iliac artery, through the uterine artery, to the ovarianartery. Alternatively, the wrist, upper arm, and shoulder region provideother locations for introduction of catheters into the arterial system.For example, catheterization of either the radial, brachial, or axillaryartery may be utilized in select cases. Catheters introduced via theseaccess points may be passed through the subclavian artery on the leftside (or via the subclavian and brachiocephalic arteries on the rightside), through the aortic arch, down the descending aorta and into theovarian arteries using standard angiographic technique.

C. Properties and Characteristics of the Ovarian Vasculature

Properties and characteristics of the ovarian and/or uterine vasculatureimpose challenges to both access and treatment methods, and tosystem/device designs. Since neuromodulation of a left and/or rightovarian nerve (e.g., ovarian plexus) may be achieved in accordance withembodiments of the present technology through intravascular access,various aspects of the design of apparatus, systems, and methods forachieving such ovarian neuromodulation are disclosed herein. Aspects ofthe technology disclosed herein address additional challenges associatedwith variation of physiological conditions and architecture across thepatient population and/or within a specific patient across time, as wellas in response to disease states, such as PCOS. For example, the designof the intravascular device and treatment protocols can address not onlymaterial/mechanical, spatial, fluid dynamic/hemodynamic and/orthermodynamic properties, but also provide particular algorithms andfeedback protocols for delivering energy and obtaining real-timeconfirmatory results of successfully delivering energy to an intendedtarget location in a patient-specific manner.

As discussed previously, a catheter may be advanced percutaneously intoeither the left or right ovarian artery via a minimally invasiveintravascular path. However, minimally invasive ovarian arterial accessmay be challenging, for example, because as compared to some otherarteries that are routinely accessed using catheters, the ovarianarteries can be tortuous, may be of relatively small diameter, and/ormay require adjustments to the length and flexibility of the catheters.Ovarian arterial anatomy also may vary significantly from patient topatient, which further complicates minimally invasive access.Significant inter-patient variation may be seen, for example, inrelative tortuosity, diameter, and/or length. Apparatus, systems andmethods for achieving ovarian neuromodulation via intravascular accesscan account for these and other aspects of ovarian arterial anatomy andits variation across the patient population when minimally invasivelyaccessing an ovarian artery. For example, spiral or helical computedtomography (CT) technology can be used to produce 3D images of thevascular features for individual patients, and intravascular path choiceand as well as device size/diameter, length, flexibility, etc. can beselected based upon the patient's specific vascular features.

In addition to complicating ovarian arterial access, specifics of theovarian anatomy also complicate establishment of stable contact betweenneuromodulatory apparatus and a luminal surface or wall of an ovarianartery. When the neuromodulatory apparatus includes an energy deliveryelement, such as an electrode, transducer, heating element or acryotherapeutic device, consistent positioning and appropriate contactforce applied by the energy or cryotherapy delivery element to thevessel wall, and adhesion between the applicator and the vessel wall canbe important for predictability. However, navigation can be impeded bythe tight space within an ovarian artery, as well as tortuosity of theartery. Furthermore, establishing consistent contact can be complicatedby patient movement, respiration, and/or the cardiac cycle because thesefactors may cause significant movement of the ovarian artery relative tothe aorta, and the cardiac cycle may transiently distend the ovarianartery (i.e., cause the wall of the artery to pulse). To address thesechallenges, the treatment device or applicator may be designed withrelative sizing and flexibility considerations. For example, the ovarianartery may have an internal diameter less than approximately 1.7 mm andthe treatment device can be delivered using a 3 French, or in somecases, a 4 French sized catheter. To address challenges associated withpatient and/or arterial movement during treatment, the treatment deviceand neuromodulation system can be configured to use sensory feedback,such as impedance and temperature, to detect instability and to alertthe operator to reposition the device and/or to temporarily stoptreatment. In other embodiments, energy delivery algorithms can bevaried in real-time to account for changes detected due to patientand/or arterial movement. In further examples, the treatment device mayinclude one or more modifications or movement resistant enhancementssuch as atraumatic friction knobs or barbs on an outside surface of thedevice for resisting movement of the device relative to the desiredtissue location, positionable balloons for inflating and holding thedevice in a consistent and stable position during treatment, or thedevice can include a cryogenic component that can temporarily freeze oradhere the device to the desired tissue location.

After accessing an ovarian artery 12 (FIGS. 1A and 1B) and facilitatingstable contact between neuromodulatory apparatus and a luminal surfaceof the artery, nerves in and around the adventitia of the artery can bemodulated via the neuromodulatory apparatus. Effectively applyingthermal treatment from within an ovarian artery is non-trivial given thepotential clinical complications associated with such treatment. Forexample, the intima and media of the ovarian artery are highlyvulnerable to thermal injury. As discussed in greater detail below, theintima-media thickness separating the vessel lumen from its adventitiameans that target ovarian nerves may be multiple millimeters distant(e.g., 1-3 mm) from the luminal surface of the artery. Sufficient energycan be delivered to or heat removed from the target ovarian nerves tomodulate the target ovarian nerves without excessively cooling orheating the vessel wall to the extent that the wall is frozen,desiccated, or otherwise potentially affected to an undesirable extent.For example, when employing energy modalities such as RF or ultrasound,energy delivery can be focused on a location further from the interiorvessel wall. In one embodiment, the majority of the RF or ultrasoundenergy can be focused on a location (e.g., a “hot spot”) 1-3 mm beyondthe interior surface of the vessel wall. The energy will dissipate fromthe hot spot in a radially decreasing manner. Thus, the targeted nervescan be modulated without damage to the luminal surface of the vessel. Apotential clinical complication associated with excessive heating isthrombus formation from coagulating blood flowing through the artery.Given that this thrombus may cause irreversible damage to the ovary,thermal treatment from within the ovarian artery can be appliedcarefully. Accordingly, the complex fluid mechanics and thermodynamicconditions present in the ovarian artery during treatment, particularlythose that may impact heat transfer dynamics at the treatment site, maybe important in applying energy (e.g., heating thermal energy) and/orremoving heat from the tissue (e.g., cooling thermal conditions) fromwithin the ovarian artery.

The neuromodulatory apparatus can also be configured to allow foradjustable positioning and repositioning of an energy delivery elementor a cryotherapeutic device within the ovarian artery since location oftreatment may also impact clinical efficacy. For example, it may betempting to apply a full circumferential treatment from within theovarian artery given that the ovarian nerves may be spacedcircumferentially around an ovarian artery. In some situations, afull-circle lesion likely resulting from a continuous circumferentialtreatment may be potentially related to ovarian artery stenosis.Therefore, the formation of more complex lesions along a longitudinaldimension of the ovarian artery via the cryotherapeutic devices orenergy delivery elements and/or repositioning of the neuromodulatoryapparatus to multiple treatment locations may be desirable. It should benoted, however, that a benefit of forming a circumferential lesion orablation may outweigh the potential of ovarian artery stenosis or therisk may be mitigated with certain embodiments or in certain patientsand forming a circumferential lesion or ablation could be a goal.Additionally, variable positioning and repositioning of theneuromodulatory apparatus may prove to be useful in circumstances wherethe ovarian artery is particularly tortuous or where there are proximalbranch vessels off the ovarian artery main vessel, making treatment incertain locations challenging.

Blood flow through an ovarian artery may be temporarily occluded for ashort time with minimal or no complications. However, occlusion for asignificant amount of time can be avoided in some cases to preventinjury to the ovary such as ischemia. It can be beneficial to avoidocclusion altogether or, if occlusion is beneficial, to limit theduration of occlusion (e.g., 2-5 minutes).

III. METHODS FOR TREATMENT OF POLYCYSTIC OVARY SYNDROME

Disclosed herein are several embodiments of methods directed totreatment of PCOS and related conditions using ovarian neuromodulation.The methods disclosed herein may represent various advantages over anumber of conventional approaches and techniques in that they allow forthe potential targeting of elevated sympathetic drive, which may eitherbe a cause of PCOS or a key mediator of the multiple manifestations ofthe disease. Also, the disclosed methods provide for localized treatmentand limited duration treatment regimens (e.g., one-time treatment),thereby reducing patient long-term treatment compliance issues.

In certain embodiments, the methods provided herein comprise performingovarian neuromodulation, thereby decreasing sympathetic ovarian nerveactivity. Ovarian neuromodulation may be repeated one or more times atvarious intervals until a desired sympathetic nerve activity level oranother therapeutic benchmark is reached. In one embodiment, forexample, a decrease in sympathetic nerve activity may be observed via amarker of sympathetic nerve activity in PCOS patients, such as decreasedlevels of plasma norepinephrine (noradrenaline). Other measures ormarkers of sympathetic nerve activity can include MSNA, norepinephrinespillover, and/or heart rate variability. In another embodiment, othermeasurable physiological parameters or markers, such as a reduction inandrogen production (e.g., lower testosterone levels) and associatedsymptoms (e.g., acne, hirsutism), increased regularity of menstruation,ovulation, decrease in number of ovarian cysts, reduction in pain levelperceived by the PCOS patient, improved blood pressure control, improvedblood glucose regulation, etc., can be used to assess efficacy of thethermal modulation treatment for PCOS patients.

In certain embodiments of the methods provided herein, ovarianneuromodulation is expected to result in a change in sympathetic nerveactivity over a specific timeframe. For example, in certain of theseembodiments, sympathetic nerve activity levels are decreased over anextended timeframe, e.g., within 1 month, 2 months, 3 months, 6 months,9 months or 12 months post-neuromodulation.

In several embodiments, the methods disclosed herein may comprise anadditional step of measuring sympathetic nerve activity levels, and incertain of these embodiments, the methods can further comprise comparingthe activity level to a baseline activity level. Such comparisons can beused to monitor therapeutic efficacy and to determine when and if torepeat the neuromodulation procedure. In certain embodiments, a baselinesympathetic nerve activity level is derived from the subject undergoingtreatment. For example, baseline sympathetic nerve activity level may bemeasured in the subject at one or more timepoints prior to treatment. Abaseline sympathetic nerve activity value may represent sympatheticnerve activity at a specific timepoint before neuromodulation, or it mayrepresent an average activity level at two or more timepoints prior toneuromodulation. In certain embodiments, the baseline value is based onsympathetic nerve activity immediately prior to treatment (e.g., afterthe subject has already been catheterized). Alternatively, a baselinevalue may be derived from a standard value for sympathetic nerveactivity observed across the population as a whole or across aparticular subpopulation. In certain embodiments, post-neuromodulationsympathetic nerve activity levels are measured in extended timeframespost-neuromodulation, e.g., 3 months, 6 months or 12 monthspost-neuromodulation.

In certain embodiments of the methods provided herein, the methods aredesigned to decrease sympathetic nerve activity to a target level. Inthese embodiments, the methods include a step of measuring sympatheticnerve activity levels post-neuromodulation (e.g., 6 monthspost-treatment, 12 months post-treatment, etc.) and comparing theresultant activity level to a baseline activity level as discussedabove. In certain of these embodiments, the treatment is repeated untilthe target sympathetic nerve activity level is reached. In otherembodiments, the methods are simply designed to decrease sympatheticnerve activity below a baseline level without requiring a particulartarget activity level.

Ovarian neuromodulation may be performed on a patient diagnosed withPCOS to reduce one or more measurable physiological parameterscorresponding to the PCOS. In some embodiments, for example, ovarianneuromodulation may prevent, increase, maintain, or reduce the number ofovarian cysts (e.g., immature ovarian follicles). A reduction in thenumber of ovarian cysts can be, for example, at least about 5%, 10%, ora greater amount as determined by qualitative or quantitative analysis(e.g., ultrasound) before and after (e.g., 1, 3, 6, or 12 months after)an ovarian neuromodulation procedure. In other embodiments, ovarianneuromodulation may prevent expansion of, maintain, or reduce an ovariancyst size with regard to a particular ovarian cyst or an average size ofsome or all ovarian cysts in a patient. A reduction in ovarian cyst sizecan be, for example, at least about 5%, 10%, or a greater amount asdetermined by qualitative or quantitative analysis (e.g., ultrasound)before and after (e.g., 1, 3, 6, or 12 months after) an ovarianneuromodulation procedure. In other embodiments, abnormally largeovarian size (>10 cm³) may be normalized (or brought closer to a normalrange).

In addition to or instead of affecting the growth or size of one or morecysts in a patient, ovarian neuromodulation may efficaciously treatother measurable physiological parameter(s) or sequela(e) correspondingto PCOS. For example, in some embodiments, ovarian neuromodulation mayreduce the severity and/or frequency of pain, reproductive/fertilityissues (e.g., oligo/amenorrhea, infertility, acne and hirsutism),metabolic issues (e.g., obesity, metabolic syndrome, insulinresistance), and cardiovascular risk (e.g., high cholesterol,hypertension). These and other results can occur at various times, e.g.,directly following ovarian neuromodulation or within about 1 month, 3months, 6 months, a year, or a longer period following ovarianneuromodulation.

As discussed previously, the progression of PCOS may be related tosympathetic overactivity and, correspondingly, the degree ofsympathoexcitation in a patient may be related to the severity of theclinical presentation of the PCOS. The ovaries may be positioned to beboth a cause (via afferent nerve fibers) and a target (via efferentsympathetic nerves) of elevated central sympathetic drive. In someembodiments, ovarian neuromodulation can be used to reduce centralsympathetic drive in a patient diagnosed with PCOS in a manner thattreats the patient for the PCOS. In some embodiments, for example, MSNAcan be reduced by at least about 10% in the patient within about threemonths after at least partially inhibiting sympathetic neural activityin nerves proximate an ovarian artery innervating the ovary. Similarly,in some instances ovarian norepinephrine spillover to plasma can bereduced at least about 20% in the patient within about three monthsafter at least partially inhibiting sympathetic neural activity innerves proximate an ovarian artery innervating the ovary. Additionally,measured ovarian norepinephrine content (e.g., assessed via biopsy,assessed in real-time via intravascular blood collection techniques,etc.) can be reduced (e.g., at least about 5%, 10%, or by at least 20%)in the patient within about three months after at least partiallyinhibiting sympathetic neural activity in nerves proximate an ovarianartery innervating the ovary.

In one prophetic example, a patient diagnosed with PCOS can be subjectedto a baseline assessment indicating a first set of measurable parameterscorresponding to the PCOS. Such parameters can include, for example,blood pressure, cholesterol levels, blood glucose levels, fasting bloodinsulin levels, measures of insulin sensitivity, duration/frequency ofmenses, testosterone levels, FSH/LH (luteinizing hormone) levels,perceived pain level, aldosterone levels, severity of hirsutism, andseverity of acne. The patient also can be tested (e.g., usingultrasound) to determine a baseline size and number of cysts of theovaries and baseline ovary size and/or volume. Following baselineassessment, the patient can be subjected to an ovarian neuromodulationprocedure. Such a procedure can, for example, include any of thetreatment modalities described herein or another treatment modality inaccordance with the present technology. The treatment can be performedon nerves proximate one or both ovaries of the patient. Following thetreatment (e.g., 1, 3, 6, or 12 months following the treatment), thepatient can be subjected to a follow-up assessment. The follow-upassessment can indicate a measurable improvement in one or morephysiological parameters corresponding to the PCOS.

The methods described herein address the sympathetic excess that isthought to be an underlying cause of PCOS or a central mechanism throughwhich PCOS manifests its multiple deleterious effects on patients. Incontrast, known therapies currently prescribed for PCOS patientstypically address only specific manifestations of PCOS. Additionally,these known therapies can have significant limitations including limitedefficacy, undesirable side effects and can be subject to adverse orundesirable drug interactions when used in combination. Additionally,conventional therapies require the patient to remain compliant with thetreatment regimen over time. In contrast, ovarian neuromodulation can bea one-time treatment that would be expected to have durable benefits toinhibit the long-term disease progression and thereby achieve afavorable patient outcome.

In some embodiments, patients diagnosed with PCOS can be treated withovarian neuromodulation alone. However, in other embodiments, patientsdiagnosed with PCOS can be treated with combinations of therapies fortreating both primary causative modes of PCOS as well as sequelae ofPCOS. For example, combinations of therapies can be tailored based onspecific manifestations of the disease in a particular patient. In aspecific example, patients having PCOS and presenting hypertension canbe treated with both anti-hypertensive therapy (e.g., drugs) and ovarianneuromodulation. In another example, ovarian neuromodulation can becombined with cholesterol lowering agents (e.g., statins), hormonaltherapy (e.g., estrogen-progestin contraceptive), fertility treatments(e.g., clomiphene, dexamethasone, FSH injections, ovarian surgery, invitro fertilization), antiandrogens (e.g., spironolactone, finasteride,cyproterone acetate, GnRH agonsists), acne-focused antibiotics,anti-acne treatments, hair growth inhibitors (e.g., eflornithinehydrochloride) and depilatories for hirsutism as well as weight loss andlifestyle change recommendations/programs.

Treatment of PCOS or related conditions may refer to preventing thecondition, slowing the onset or rate of development of the condition,reducing the risk of developing the condition, preventing or delayingthe development of symptoms associated with the condition, reducing orending symptoms associated with the condition, generating a complete orpartial regression of the condition, or some combination thereof.

IV. SELECTED EMBODIMENTS OF OVARIAN NEUROMODULATION SYSTEMS AND DEVICES

FIG. 3 is a partially schematic diagram illustrating a neuromodulationsystem 100 (“system 100”) configured in accordance with an embodiment ofthe present technology. The system 100 can include a treatment device102, an energy source or console 104 (e.g., a RF energy generator, acryotherapy console, etc.), and a cable 106 extending between thetreatment device 102 and the console 104. The treatment device 102 caninclude a handle 108, a neuromodulation assembly 110, and an elongatedshaft 112 extending between the handle 108 and the neuromodulationassembly 110. The shaft 112 can be configured to locate theneuromodulation assembly 110 intravascularly at a treatment location(e.g., in or near the ovarian artery, the ovarian vein, and/or anothersuitable structure), and the neuromodulation assembly 110 can beconfigured to provide or support therapeutically-effectiveneuromodulation at the treatment location. In some embodiments, theshaft 112 and the neuromodulation assembly 110 can be 3, 4, 5, 6, or 7French or another suitable size. Furthermore, the shaft 112 and theneuromodulation assembly 110 can be partially or fully radiopaque and/orcan include radiopaque markers corresponding to measurements, e.g.,every 5 cm.

Intravascular delivery can include percutaneously inserting a guide wire(not shown) within the vasculature and moving the shaft 112 and theneuromodulation assembly 110 along the guide wire until theneuromodulation assembly 110 reaches the treatment location. Forexample, the shaft 112 and the neuromodulation assembly 110 can includea guide-wire lumen (not shown) configured to receive the guide wire inan over-the-wire (OTW) or rapid-exchange (RX) configuration. Other bodylumens (e.g., ducts or internal chambers) can be treated, for example,by non-percutaneously passing the shaft 112 and neuromodulation assembly110 through externally accessible passages of the body or other suitablemethods. In some embodiments, a distal end of the neuromodulationassembly 110 can terminate in an atraumatic rounded tip or cap (notshown). The treatment device 102 can also be a steerable ornon-steerable catheter device (e.g., a guide catheter) configured foruse without a guide wire.

The neuromodulation assembly 110 can have a single state orconfiguration, or it can be convertible between a plurality of states orconfigurations. For example, the neuromodulation assembly 110 can beconfigured to be delivered to the treatment location in a delivery stateand to provide or support therapeutically-effective neuromodulation in adeployed state. In these and other embodiments, the neuromodulationassembly 110 can have different sizes and/or shapes in the delivery anddeployed states. For example, the neuromodulation assembly 110 can havea low-profile configuration in the delivery state and an expandedconfiguration in the deployed state. In another example, theneuromodulation assembly 110 can be configured to deflect into contactwith a vessel wall in a delivery state. The neuromodulation assembly 110can be converted (e.g., placed or transformed) between the delivery anddeployed states via remote actuation, e.g., using an actuator 114 of thehandle 108. The actuator 114 can include a knob, a pin, a lever, abutton, a dial, or another suitable control component. In otherembodiments, the neuromodulation assembly 110 can be transformed betweenthe delivery and deployed states using other suitable mechanisms ortechniques.

In some embodiments, the neuromodulation assembly 110 can include anelongated member (not shown) that can be configured to curve (e.g.,arch) in the deployed state, e.g., in response to movement of theactuator 114. For example, the elongated member can be at leastpartially helical/spiral in the deployed state. In other embodiments,the neuromodulation assembly 110 can include a balloon (not shown) thatcan be configured to be at least partially inflated in the deployedstate. An elongated member, for example, can be well suited for carryingone or more heating elements, electrodes or transducers and fordelivering direct heat, electrode-based or transducer-based treatment. Aballoon, for example, can be well suited for containing refrigerant(e.g., during or shortly after liquid-to-gas phase change) and fordelivering cryotherapeutic treatment. A balloon can also be used in someembodiments for carrying suitable RF conducting electrodes. In someembodiments, the neuromodulation assembly 110 can be configured forintravascular and/or transvascular delivery of chemicals. For example,the neuromodulation assembly 110 can include one or more openings (notshown), and chemicals (e.g., drugs or other agents) can be deliverablethrough the openings. For transvascular delivery, the neuromodulationassembly 110 can include one or more needles (not shown) (e.g.,retractable needles) and the openings can be at end portions of theneedles.

The console 104 is configured to control, monitor, supply, or otherwisesupport operation of the treatment device 102. In some embodiments, theconsole 104 can be separate from and in communication with the treatmentdevice 102. In other embodiments, the console 104 can be containedwithin or be a component of the treatment device 102. In still furtherembodiments, the treatment device 102 can be self-contained and/orotherwise configured for operation without connection to the console104. As shown in FIG. 3, the console 104 can include a primary housing116 having a display 118. The system 100 can include a control device120 along the cable 106 configured to initiate, terminate, and/or adjustoperation of the treatment device 102 directly and/or via the console104. In other embodiments, the system 100 can include another suitablecontrol mechanism. For example, the control device 120 can beincorporated into the handle 108. The console 104 can be configured toexecute an automated control algorithm 122 and/or to receive controlinstructions from an operator. Furthermore, the console 104 can beconfigured to provide feedback to an operator before, during, and/orafter a treatment procedure via the display 118 and/or anevaluation/feedback algorithm 124. In some embodiments, the console 104can include a processing device (not shown) having processing circuitry,e.g., a microprocessor. The processing device can be configured toexecute stored instructions relating to the control algorithm 122 and/orthe evaluation/feedback algorithm 124. Furthermore, the console 104 canbe configured to communicate with the treatment device 102, e.g., viathe cable 106. For example, the neuromodulation assembly 110 of thetreatment device 102 can include a sensor (not shown) (e.g., a recordingelectrode, a temperature sensor, a pressure sensor, or a flow ratesensor) and a sensor lead (not shown) (e.g., an electrical lead or apressure lead) configured to carry a signal from the sensor to thehandle 108. The cable 106 can be configured to carry the signal from thehandle 108 to the console 104.

The console 104 can have different configurations depending on thetreatment modality of the treatment device 102. For example, when thetreatment device 102 is configured for electrode-based ortransducer-based treatment, the console 104 can include an energygenerator (not shown) configured to generate RF energy, pulsed RFenergy, microwave energy, optical energy, ultrasound energy (e.g.,intravascularly delivered ultrasound, extracorporeal ultrasound, HIFU),magnetic energy, direct heat energy, or another suitable type of energy.In some embodiments, for example, the console 104 can include a RFgenerator operably coupled to one or more electrodes (not shown) of theneuromodulation assembly 110.

When the treatment device 102 is configured for cryotherapeutictreatment, the console 104 can include a refrigerant reservoir (notshown) and can be configured to supply the treatment device 102 withrefrigerant, e.g., pressurized refrigerant in liquid or substantiallyliquid phase. Similarly, when the treatment device 102 is configured forchemical-based treatment, the console 104 can include a chemicalreservoir (not shown) and can be configured to supply the treatmentdevice 102 with one or more chemicals. In some embodiments, thetreatment device 102 can include an adapter (not shown) (e.g., a luerlock) configured to be operably coupled to a syringe (not shown). Theadapter can be fluidly connected to a lumen (not shown) of the treatmentdevice 102, and the syringe can be used, for example, to manuallydeliver one or more chemicals to the treatment location, to withdrawmaterial from the treatment location, to inflate a balloon (not shown)of the neuromodulation assembly 110, to deflate a balloon of theneuromodulation assembly 110, or for another suitable purpose. In otherembodiments, the console 104 can have other suitable configurations.

In certain embodiments, a neuromodulation device for use in the methodsdisclosed herein may combine two or more energy modalities. For example,the device may include both a hyperthermic source of ablative energy anda hypothermic source, making it capable of, for example, performing bothRF neuromodulation and cryo-neuromodulation. The distal end of thetreatment device may be straight (for example, a focal catheter),expandable (for example, an expanding mesh or cryoballoon), or have anyother configuration. For example, the distal end of the treatment devicecan be at least partially helical/spiral in the deployed state.Additionally or alternatively, the treatment device may be configured tocarry out one or more non-ablative neuromodulatory techniques. Forexample, the device may comprise a means for diffusing a drug orpharmaceutical compound at the target treatment area (e.g., a distalspray nozzle).

V. SELECTED EXAMPLES OF TREATMENT PROCEDURES FOR OVARIAN NEUROMODULATION

Referring back to FIGS. 1A and 1B and in some embodiments, the shaft 18and the therapeutic element 20 can be portions of a treatment device atleast partially corresponding to the treatment device 102 shown in FIG.3. The therapeutic element 20, for example, can be configured toradially expand into a deployed state at the treatment location. In thedeployed state, the therapeutic element 20 can be configured to contactan inner wall of a vessel of the ovarian vasculature and to form asuitable lesion or pattern of lesions without the need forrepositioning. For example, the therapeutic element 20 can be configuredto form a single lesion or a series of lesions, e.g., overlapping ornon-overlapping. In some embodiments, the lesion or pattern of lesionscan extend around generally the entire circumference of the vessel, butcan still be non-circumferential at longitudinal segments or zones alonga lengthwise portion of the vessel. This can facilitate precise andefficient treatment with a low possibility of vessel stenosis. In otherembodiments, the therapeutic element 20 can be configured form apartially-circumferential lesion or a fully-circumferential lesion at asingle longitudinal segment or zone of the vessel. During treatment, thetherapeutic element 20 can be configured for partial or full occlusionof a vessel. Partial occlusion can be useful, for example, to reduceovarian ischemia, while full occlusion can be useful, for example, toreduce interference (e.g., warming or cooling) caused by blood flowthrough the treatment location. In some embodiments, the therapeuticelement 20 can be configured to cause therapeutically-effectiveneuromodulation (e.g., using ultrasound energy) without contacting avessel wall.

A variety of other suitable treatment locations are also possible in andaround the ovarian artery 12, the ovarian vein 14, and/or other suitablestructures. For example, since the ovarian artery 12 becomes narrowerand more tortuous further from the aorta, it can be more convenient insome cases to treat the ovarian artery 12 at its trunk. Furthermore, atreatment procedure can include treatment at any suitable number oftreatment locations, e.g., a single treatment location, two treatmentlocations, or more than two treatment locations. In some embodiments,different treatment locations can correspond to different portions ofthe ovarian artery 12, the ovarian vein, and/or other suitablestructures proximate tissue having relatively high concentrations ofovarian nerves. The shaft 18 can be steerable (e.g., via one or morepull wires, a steerable guide or sheath catheter, etc.) and can beconfigured to move the therapeutic element 20 between treatmentlocations. At each treatment location, the therapeutic element 20 can beactivated to cause modulation of nerves proximate the treatmentlocation. Activating the therapeutic element 20 can include, forexample, heating, cooling, stimulating, or applying another suitabletreatment modality at the treatment location. Activating the therapeuticelement 20 can further include applying various energy modalities atvarying power levels, intensities and for various durations forachieving modulation of nerves proximate the treatment location. In someembodiments, power levels, intensities and/or treatment duration can bedetermined and employed using various algorithms for ensuring modulationof nerves at select distances (e.g., depths) away from the treatmentlocation. Furthermore, as noted previously, in some embodiments, thetherapeutic element 20 can be configured to introduce (e.g., inject) achemical (e.g., a drug or other agent) into target tissue at thetreatment location. Such chemicals or agents can be applied at variousconcentrations depending on treatment location and the relative depth ofthe target nerves.

The therapeutic element 20 can be positioned at a treatment locationwithin the ovarian artery 12, for example, via a catheterization pathincluding a femoral artery and the aorta, a catheterization pathincluding the internal iliac artery and the uterine artery, or anothersuitable catheterization path, e.g., a radial or brachialcatheterization path. Catheterization can be guided, for example, usingimaging, e.g., magnetic resonance, computed tomography, fluoroscopy,ultrasound, intravascular ultrasound, optical coherence tomography, oranother suitable imaging modality. The therapeutic element 20 can beconfigured to accommodate the anatomy of the ovarian artery 12, theovarian vein 14, and/or another suitable structure. For example, thetherapeutic element 20 can include a balloon (not shown) configured toinflate to a size generally corresponding to the internal size of theovarian artery 12, the ovarian vein 14, and/or another suitablestructure. In some embodiments, the therapeutic element 20 can be animplantable device and a treatment procedure can include locating thetherapeutic element 20 at the treatment location using the shaft 18fixing the therapeutic element 20 at the treatment location, separatingthe therapeutic element 20 from the shaft 18, and withdrawing the shaft18. Other treatment procedures for modulation of ovarian nerves inaccordance with embodiments of the present technology are also possible.

As mentioned previously, the methods disclosed herein may use a varietyof suitable energy modalities, including RF energy, microwave energy,laser, optical energy, ultrasound energy (e.g., intravascularlydelivered ultrasound, extracorporeal ultrasound, HIFU), magnetic energy,direct heat, cryotherapy, or a combination thereof. Alternatively or inaddition to these techniques, the methods may utilize one or morenon-ablative neuromodulatory techniques. For example, the methods mayutilize non-ablative SNS neuromodulation by removal of target nerves(e.g., surgically), injection of target nerves with a destructive drugor pharmaceutical compound, or treatment of the target nerves withnon-ablative energy modalities (e.g., laser or light energy). In certainembodiments, the amount of reduction of the sympathetic nerve activitymay vary depending on the specific technique being used.

FIG. 4 is a block diagram illustrating a method 400 of modulatingovarian nerves using the system 100 described above with reference toFIGS. 1A-3. With reference to FIGS. 1A-4 together, the method 400 canoptionally include diagnosing PCOS in a patient (if not yet determined)and/or selecting a suitable candidate PCOS patient for performingovarian neuromodulation (block 402). The method 400 can includeintravascularly locating the neuromodulation assembly 110 in a deliverystate (e.g., low-profile configuration) at a first target site in ornear a first ovarian blood vessel (e.g., first ovarian artery) (block405). The treatment device 102 and/or portions thereof (e.g., theneuromodulation assembly 110) can be inserted into a guide catheter orsheath to facilitate intravascular delivery of the neuromodulationassembly 110. In certain embodiments, for example, the treatment device102 can be configured to fit within an 8 Fr guide catheter or smaller(e.g., 7 Fr, 6 Fr, etc.) to access small peripheral vessels. A guidewire (not shown), if present, can be used to manipulate and enhancecontrol of the shaft 112 and the neuromodulation assembly 110 (e.g., inan over-the-wire or a rapid-exchange configuration). In someembodiments, radiopaque markers and/or markings on the treatment device102 and/or the guide wire can facilitate placement of theneuromodulation assembly 110 at the first target site (e.g., a firstovarian artery of a PCOS patient). In some embodiments, a contrastmaterial can be delivered distally beyond the neuromodulation assembly110, and fluoroscopy and/or other suitable imaging techniques can beused to aid in placement of the neuromodulation assembly 110 at thefirst target site.

The method 400 can further include connecting the treatment device 102to the console 104 (block 410), and determining whether theneuromodulation assembly 110 is in the correct position at the targetsite and/or whether the neuromodulation assembly (e.g., electrodes orcryotherapy balloon) is functioning properly (block 415). Once theneuromodulation assembly 110 is properly located at the first targetsite and no malfunctions are detected, the console 104 can bemanipulated to initiate application of an energy field to the targetsite to cause electrically-induced and/or thermally-induced partial orfull denervation of the ovary (e.g., using electrodes or cryotherapeuticdevices). Accordingly, heating and/or cooling of the neuromodulationassembly 110 causes modulation of ovarian nerves at the first targetsite to cause partial or full denervation of the ovary associated withthe first target site (block 420).

In one example, the treatment device 102 can be an RF energy emittingdevice and RF energy can be delivered through energy delivery elementsor electrodes to one or more locations along the inner wall of the firstovarian artery for predetermined periods of time (e.g., 120 seconds). Insome embodiments, multiple treatments (e.g., 4-6) may be administered inboth the left and right ovarian arteries to achieve a desired coverage.An objective of a treatment may be, for example, to heat tissue to adesired depth (e.g., at least about 3 mm) to a temperature (e.g., about65° C.) that would modulate one or more nerve fibers associated with oradjacent to one or more lesions formed in the vessel wall. A clinicalobjective of the procedure typically is to neuromodulate a sufficientnumber of ovarian nerves (either efferent or afferent nerves) to cause areduction in sympathetic tone or drive to the ovaries without, forexample, disrupting ovarian function and while minimizing vessel trauma.If the objective of a treatment is met (e.g., tissue is heated to about65° C. to a depth of about 3 mm) the probability of modulating ovariannerve tissue (e.g., altering nerve function) is high. In someembodiments, a single neuromodulation treatment procedure can providefor sufficient modulation of target sympathetic nerves (e.g., modulationof a sufficient number of nerve fibers) to provide a desired clinicaloutcome. In other embodiments, more than one treatment may be beneficialfor modulating a desired number or volume of target sympathetic nervefibers, and thereby achieve clinical success. In other embodiments, anobjective may include reducing or eliminating ovarian nerve functioncompletely.

In a specific example of using RF energy for ovarian nerve modulation, aclinician can commence treatment which causes the control algorithm 122(FIG. 3) to initiate instructions to the generator (not shown) togradually adjust its power output to a first power level (e.g., 5 watts)over a first time period (e.g., 15 seconds). The power increase duringthe first time period is generally linear. As a result, the generatorincreases its power output at a generally constant rate of power/time,i.e., in a linear manner. Alternatively, the power increase may benon-linear (e.g., exponential or parabolic) with a variable rate ofincrease. Once the first power level and the first time are achieved,the algorithm may hold at the first power level until a secondpredetermined period of time has elapsed (e.g., 3 seconds). At theconclusion of the second period of time, power is again increased by apredetermined increment (e.g., 1 watt) to a second power level over athird predetermined period of time (e.g., 1 second). This power ramp inpredetermined increments of about 1 watt over predetermined periods oftime may continue until a maximum power P_(MAX) is achieved or someother condition is satisfied. In one embodiment, P_(MAX) is 8 watts. Inanother embodiment, P_(MAX) is 10 watts, or in a further embodiment,P_(MAX) is 6.5 watts. In some embodiments, P_(MAX) can be about 6 wattsto about 10 watts. Optionally, the power may be maintained at themaximum power P_(MAX) for a desired period of time or up to the desiredtotal treatment time (e.g., up to about 120 seconds) or until aspecified temperature is reached or maintained for a specified timeperiod.

In another specific example, the treatment device 102 can be a cryogenicdevice and cryogenic cooling can be applied for one or more cycles(e.g., for 30 second increments, 60 second increments, 90 secondincrements, etc.) in one or more locations along the circumferenceand/or length of the first ovarian artery. The cooling cycles can be,for example, fixed periods or can be fully or partially dependent ondetected temperatures (e.g., temperatures detected by a thermocouple(not shown) of the neuromodulation assembly 110). In some embodiments, afirst stage can include cooling tissue until a first target temperatureis reached. A second stage can include maintaining cooling for a setperiod, such as 15-180 seconds (e.g., 90 seconds). A third stage caninclude terminating or decreasing cooling to allow the tissue to warm toa second target temperature higher than the first target temperature. Afourth stage can include continuing to allow the tissue to warm for aset period, such as 10-120 seconds (e.g., 60 seconds). A fifth stage caninclude cooling the tissue until the first target temperature (or adifferent target temperature) is reached. A sixth stage can includemaintaining cooling for a set period, such as 15-180 seconds (e.g., 90seconds). A seventh stage can, for example, include allowing the tissueto warm completely (e.g., to reach a body temperature).

The neuromodulation assembly 110 can then be located at a second targetsite in or near a second ovarian blood vessel (e.g., second ovarianartery) (block 425), and correct positioning of the assembly 110 can bedetermined (block 430). In selected embodiments, a contrast material canbe delivered distally beyond the neuromodulation assembly 110 andfluoroscopy and/or other suitable imaging techniques can be used tolocate the second ovarian artery. The method 400 continues by applyingtargeted heat or cold to effectuate ovarian neuromodulation at thesecond target site to cause partial or full denervation of the ovaryassociated with the second target site (block 435).

After providing the therapeutically-effective neuromodulation energy(e.g., cryogenic cooling, RF energy, ultrasound energy, etc.), themethod 400 may also include determining whether the neuromodulationtherapeutically treated the patient for PCOS or otherwise sufficientlymodulated nerves or other neural structures proximate the first andsecond target sites (block 440). For example, the process of determiningwhether the neuromodulation therapeutically treated the nerves caninclude determining whether nerves were sufficiently modulated orotherwise disrupted to reduce, suppress, inhibit, block or otherwiseaffect the afferent and/or efferent ovarian signals (e.g., by evaluationof suitable biomarkers, stimulation and recording of nerve signals,etc.). In a further embodiment, patient assessment could be performed attime intervals (e.g., 1 month, 3 months, 6 months, 12 months) followingneuromodulation treatment. For example, the patient can be assessed formeasurements of perceived pain, blood pressure control, blood glucoselevels, androgen levels (e.g., testosterone levels), imaging-basedmeasurements of ovarian cyst size and number, imaging-based measurementsof ovary size and/or volume, reversal of infertility, regularity ofmenses, improvement in hirsutism, aldosterone levels, and measures ofsympathetic activity (e.g., MSNA, and/or ovarian norepinephrinespillover to plasma, whole body norepinephrine spillover, and heart ratevariability).

In other embodiments, various steps in the method 400 can be modified,omitted, and/or additional steps may be added. In further embodiments,the method 400 can have a delay between applyingtherapeutically-effective neuromodulation energy at a first target siteat or near a first ovarian artery and applying therapeutically-effectiveneuromodulation energy at a second target site at or near a secondovarian artery. For example, neuromodulation of the first ovarian arterycan take place at a first treatment session, and neuromodulation of thesecond ovarian artery can take place a second treatment session at alater time.

As discussed previously, treatment procedures for modulation of ovariannerves in accordance with embodiments of the present technology areexpected to improve at least one condition associated with ovariansympathetic activity (e.g., overactivity or hyperactivity) and/orcentral sympathetic activity (e.g., overactivity or hyperactivity). Forexample, with respect to PCOS, modulation of ovarian nerves inaccordance with embodiments of the present technology is expected toreduce expansion of, maintain the size of, or reduce the size of anovarian cyst in a patient. In a particular example, the size of anovarian cyst in a patient is expected to be reduced at least about 5%within about three months after modulating the ovarian nerves in thepatient. With respect to central sympathetic activity (e.g.,overactivity or hyperactivity), for example, modulation of ovariannerves is expected to reduce MSNA and/or whole body norepinephrinespillover in patients. These and other clinical effects are expected tobe detectable immediately after a treatment procedure or after a delay,e.g., of 1, 2, or 3 months. In some instances, it may be useful torepeat ovarian neuromodulation at the same treatment location or adifferent treatment location after a suitable delay, e.g., 1, 2, or 3years. In still other embodiments, however, other suitable treatmentregimens or techniques may be used.

VI. PERTINENT ANATOMY AND PHYSIOLOGY

The following discussion provides further details regarding pertinentpatient anatomy and physiology. This section is intended to supplementand expand upon the previous discussion regarding the relevant anatomyand physiology, and to provide additional context regarding thedisclosed technology and the therapeutic benefits associated withovarian neuromodulation.

A. The Sympathetic Nervous System

The SNS is a branch of the autonomic nervous system along with theenteric nervous system and parasympathetic nervous system. It is alwaysactive at a basal level (called sympathetic tone) and becomes moreactive during times of stress. Like other parts of the nervous system,the SNS operates through a series of interconnected neurons. Sympatheticneurons are frequently considered part of the peripheral nervous system(PNS), although many lie within the central nervous system (CNS).Sympathetic neurons of the spinal cord (which is part of the CNS)communicate with peripheral sympathetic neurons via a series ofsympathetic ganglia. Within the ganglia, spinal cord sympathetic neuronsjoin peripheral sympathetic neurons through synapses. Spinal cordsympathetic neurons are therefore called presynaptic (or preganglionic)neurons, while peripheral sympathetic neurons are called postsynaptic(or postganglionic) neurons.

At synapses within the sympathetic ganglia, preganglionic sympatheticneurons release acetylcholine, a chemical messenger that binds andactivates nicotinic acetylcholine receptors on postganglionic neurons.In response to this stimulus, postganglionic neurons principally releasenoradrenaline (norepinephrine). Prolonged activation may elicit therelease of adrenaline from the adrenal medulla.

Once released, norepinephrine binds adrenergic receptors on peripheraltissues. Binding to adrenergic receptors causes a neuronal and hormonalresponse. The physiologic manifestations include pupil dilation,increased heart rate, occasional vomiting, and increased blood pressure.Increased sweating is also seen due to binding of cholinergic receptorsof the sweat glands.

The SNS is responsible for up- and down-regulation of many homeostaticmechanisms in living organisms. Fibers from the SNS innervate tissues inalmost every organ system, providing at least some regulatory functionto physiological features as diverse as pupil diameter, gut motility,and urinary output. This response is also known as the sympatho-adrenalresponse of the body, as the preganglionic sympathetic fibers that endin the adrenal medulla (but also all other sympathetic fibers) secreteacetylcholine, which activates the secretion of adrenaline (epinephrine)and to a lesser extent noradrenaline (norepinephrine). Therefore, thisresponse that acts primarily on the cardiovascular system is mediateddirectly via impulses transmitted through the SNS and indirectly viacatecholamines secreted from the adrenal medulla.

Science typically looks at the SNS as an automatic regulation system,that is, one that operates without the intervention of consciousthought. Some evolutionary theorists suggest that the SNS operated inearly organisms to maintain survival as the SNS is responsible forpriming the body for action. One example of this priming is in themoments before waking, in which sympathetic outflow spontaneouslyincreases in preparation for action.

1. The Sympathetic Chain

As shown in FIG. 5, the SNS provides a network of nerves that allows thebrain to communicate with the body. Sympathetic nerves originate insidethe vertebral column, toward the middle of the spinal cord in theintermediolateral cell column (or lateral horn), beginning at the firstthoracic segment of the spinal cord and are thought to extend to thesecond or third lumbar segments. Because its cells begin in the thoracicand lumbar regions of the spinal cord, the SNS is said to have athoracolumbar outflow. Axons of these nerves leave the spinal cordthrough the anterior rootlet/root. They pass near the spinal (sensory)ganglion, where they enter the anterior rami of the spinal nerves.However, unlike somatic innervation, they quickly separate out throughwhite rami connectors that connect to either the paravertebral (whichlie near the vertebral column) or prevertebral (which lie near theaortic bifurcation) ganglia extending alongside the spinal column.

In order to reach the target organs and glands, the axons travel longdistances in the body. Many axons relay their message to a second cellthrough synaptic transmission. The first cell (the presynaptic cell)sends a neurotransmitter across the synaptic cleft (the space betweenthe axon terminal of the first cell and the dendrite of the second cell)where it activates the second cell (the postsynaptic cell). The messageis then propagated to the final destination.

In the SNS and other neuronal networks of the peripheral nervous system,these synapses are located at sites called ganglia, discussed above. Thecell that sends its fiber to a ganglion is called a preganglionic cell,while the cell whose fiber leaves the ganglion is called apostganglionic cell. As mentioned previously, the preganglionic cells ofthe SNS are located between the first thoracic (T1) segment and thirdlumbar (L3) segments of the spinal cord. Postganglionic cells have theircell bodies in the ganglia and send their axons to target organs orglands. The ganglia include not just the sympathetic trunks but also thecervical ganglia (superior, middle and inferior), which sendssympathetic nerve fibers to the head and thorax organs, and the celiacand mesenteric ganglia (which send sympathetic fibers to the gut).

2. Innervation of the Ovaries

The ovaries and part of the fallopian tubes and broad ligament of theuterus are innervated by the ovarian plexus, a network of nerve fibersaccompanying the ovarian vessels and derived from the aortic and renalplexuses. As FIG. 6 shows, the blood supply to the ovary is provided bythe ovarian artery. The ovarian plexus is an autonomic plexus thatsurrounds the ovarian artery and is carried in the suspensory ligament.The ovarian plexus extends along the ovarian artery until it arrives atthe substance of the ovary. Fibers contributing to the ovarian plexusarise from the renal plexus, celiac ganglion, the superior mesentericganglion, the aorticorenal ganglion and the aortic plexus. The ovarianplexus, also referred to as the ovarian nerve, is predominantlycomprised of sympathetic nerve fibers.

Preganglionic neuronal cell bodies are located in the intermediolateralcell column of the spinal cord. Preganglionic axons pass through theparavertebral ganglia (they do not synapse) to become the lessersplanchnic nerve, the least splanchnic nerve, the first lumbarsplanchnic nerve, and the second lumbar splanchnic nerve, and theytravel to the celiac ganglion, the superior mesenteric ganglion, and theaorticorenal ganglion. Postganglionic neuronal cell bodies exit theceliac ganglion, the superior mesenteric ganglion, and the aorticorenalganglion to the renal plexus, which are distributed to the renalvasculature, and give rise to the ovarian plexus which is distributed tothe ovary and the fundus of the uterus.

3. Ovarian Sympathetic Neural Activity

Messages travel through the SNS in a bidirectional flow. Efferentmessages may trigger changes in different parts of the bodysimultaneously. For example, the SNS may accelerate heart rate; widenbronchial passages; decrease motility (movement) of the large intestine;constrict blood vessels; increase peristalsis in the esophagus; causepupil dilation, cause piloerection (i.e., goose bumps), causeperspiration (i.e., sweating), and raise blood pressure. Afferentmessages carry signals from various organs and sensory receptors in thebody to other organs and, particularly, the brain.

Hypertension, heart failure and chronic kidney disease are a few of manydisease states that result from chronic activation of the SNS,especially the renal sympathetic nervous system. Chronic activation ofthe SNS is a maladaptive response that drives the progression of thesedisease states. Pharmaceutical management of therenin-angiotensin-aldosterone system (RAAS) has been a longstanding, butsomewhat ineffective, approach for reducing overactivity of the SNS.

Some experimental data and clinical results are suggestive of the rolethe sympathetic nervous system has as a contributor to the complexpathophysiology of PCOS. For example, studies measuring efferentpostganglionic MSNA in PCOS patients revealed that PCOS is associatedwith high MSNA. Elevated testosterone and cholesterol lipid levels wereidentified as independent predictors of MSNA in PCOS. Additionalevidence suggests that there is a greater density of catecholaminergicnerve fibers in polycystic ovaries and altered peripheral catecholaminesecretion in adolescent PCOS patients. It has also been shown thatactivation of the sympathetic neurons innervating the ovary precedes thedevelopment of cystic ovaries in rats.

VII. EXAMPLES Example 1: Effect of Renal Neuromodulation on PCOS

This section describes an example of the outcome of renalneuromodulation on two patients diagnosed with PCOS and observedapproximately three months following renal neuromodulation (Schlaich etal., 2011, Journal of Hypertension 29: 991-996; incorporated herein byreference in its entirety).

Two obese patients with hypertension and PCOS were offered to undergo arenal neuromodulation procedure. Prior to renal neuromodulation, patient1 (27 years old) weighed 97.6 kg and had a BMI of 36.2 kg/m², andpatient 2 (34 years old) weighted 90.4 kg and had a BMI of 34.3 kg/m².PCOS was previously diagnosed in both patients by a combination ofclinical and biochemical signs of hyperandrogenism and polycysticovaries on ultrasound imaging. Lifestyle and medication were stable forat least four weeks prior to the baseline assessment and the patientsdid not change their lifestyle and medication during the three monthsbetween the renal neuromodulation and the follow-up assessment.Following the baseline assessment of sympathetic nerve activity (usingmicroneurography (MSNA) and norepinephrine spillover measurements) andinsulin sensitivity (using euglycemic hyperinsulinemic clamp), bothpatients underwent bilateral radiofrequency renal neuromodulationwithout any periprocedural complications. Measurements of cystatin-C,creatinine clearance, and urinary albumin creatinine ratio were alsoobtained. All measurements performed at the baseline assessment wererepeated three months after the renal neuromodulation at the follow-upassessment.

MSNA was recorded using microneurography in the peroneal nerve. A tracerinfusion of 3H-labeled norepinephrine (levo-7-3HNE, specific activity of11-25 Ci/mmol; New England Nuclear, Boston, Mass., USA) was given via aperipheral vein at 0.6-0.8 μCi/min, after a priming bolus of 12 μCi, forthe measurement of total body norepinephrine spillover by isotopedilution. The euglycemic hyperinsulinemic clamp technique was used toquantify in-vivo insulin sensitivity. After a bolus injection of 9 mU/kginsulin (Actrapid HM100 U/ml; Novo Nordisk, Baulkham Hills, New SouthWales, Australia), a constant infusion rate of 40 mU/m² per minute wasmaintained over two hours. Blood glucose concentration was clamped atthe euglycemic level of 5 mmol/l through the variable infusion of 25%glucose and measured every 5 minutes using an autoanalyzer (ABL 800Basic; Radiometer, Copenhagen). Peripheral insulin sensitivity wasderived from the average glucose infusion rate during the final 20minutes, corrected for glucose space, and normalized to body weight.

Both patients had uncontrolled clinic blood pressure levels at baseline(e.g., Patient 1 had a baseline blood pressure of 183/107 mmHg, Patient2 had a baseline blood pressure of 167/123 mmHg) despite a therapeuticregimen consisting of at least four different antihypertensive drugclasses and had a BMI in the obese range (FIG. 7A). For example, Patient1 was taking a regimen of Irbesartan/HCT, Methyldopa, Prazosin andSpironolactone, and Patient 2 was taking a regimen of Spironolactone,Amlodipine/valsartan, Ramipril and Moxonidine. Of note, Patient 1 wasintolerant to calcium channel blockers and Patient 2 to thiazidediuretics. Neither of the patients was on oral antidiabetic drugs orinsulin before or during the study. Both patients had normal renalfunction as indicated by cystatin-C levels below 1 mg/l. As shown inFIGS. 7B and 7C, indices of sympathetic nervous system activation weresubstantially elevated in both patients with an approximately 2.5 to3-fold increase above levels typically found in normotensive healthycontrols for both MSNA (normal being about 15 to 20 bursts/min) andwhole body norepinephrine (NE) spillover (normal being about 300 to 600ng/min).

Bilateral renal neuromodulation resulted in mild-to-moderate reductionsin systolic blood pressure and diastolic blood pressure in the twopatients at the three-month follow-up (FIG. 7A). For example, 3 monthspost renal neuromodulation, Patient 1 had a blood pressure of 175/81mmHg, and Patient 2 had a blood pressure of 140/102 mmHg. MSNA wasreduced in both patients by about 17% and about 33%, respectively (FIG.7B) after renal neuromodulation. Whole body NE spillover was well abovethe upper normal limit of around 600 ng/min in both patients at baselineand reduced in both patients by 5% and 8% directly after renalneuromodulation (FIG. 7C), and by 28% in the one patient who had wholebody NE spillover repeated at 12 weeks, suggesting that sympatheticactivation may decrease further over time.

Changes in metabolic parameters following bilateral renalneuromodulation are illustrated in FIGS. 8A-8F. There was no substantialchange in body weight with Patient 1 experiencing a minor reduction(e.g., 2.5 kg reduction) and Patient 2 experiencing a minor increase(e.g., 2.4 kg increase) in body weight at the three-month follow-up(FIG. 8A). Fasting plasma glucose levels were lower in both patients atthe three-month follow-up compared to baseline (FIG. 8B). Insulinsensitivity, as assessed by euglycemic hyperinsulinemic clamp, increasedby 20.9% and 14.4%, respectively, in both patients at the three-monthfollow-up after renal neuromodulation (FIG. 8C). There was no indicationof renal function impairment after renal neuromodulation with cystatin-Clevels being unchanged or reduced (FIG. 8D). Assessment of creatinineclearance at baseline, though limited in accurately assessing glomerularfiltration, revealed a state of hyperfiltration in Patient 1 (216 and132 ml/min, respectively), which was normalized three months after renalneuromodulation (FIG. 8E). Patient 1 presented with microalbuminuria atbaseline, which was substantially reduced by approximately 50% at thethree-month follow-up after renal neuromodulation (FIG. 8F).

As discussed above, PCOS has been associated with increased sympatheticnerve activity. The reduction of central sympathetic drive associatedwith renal neuromodulation may highlight the relevance of sympatheticactivation in blood pressure control and glucose metabolism in patientswith PCOS. Indeed, sympathetic activation may be a link between obesity,hypertension, and insulin resistance, which are frequently encounteredin PCOS and represent an important target for the prevention andtreatment of the metabolic and cardiovascular features of PCOS. Thefindings discussed in this example suggest an inhibitory effect of renalneuromodulation on indices of sympathetic activation that was associatedwith simultaneous reduction in both blood pressure and insulinresistance. Similar findings on insulin resistance have been reportedwith pharmaceutical agents that reduce central sympathetic drive, suchas moxonidine.

The findings suggest that reduction of sympathetic activity, as measuredby MSNA and norepinephrine spillover, via renal sympatheticneuromodulation resulted in improved fasting glucose levels and insulinsensitivity in the absence of significant changes in body weight and anyalterations in lifestyle or antihypertensive medication. A likelyexplanation for the substantial improvement in insulin sensitivity inresponse to renal neuromodulation is a combination of beneficial effectsof sympathoinhibition and reduced release of norepinephrine on regionalhemodynamics and direct cellular effects.

In the human forearm, increased norepinephrine release typically resultsin a substantial reduction in forearm blood flow (e.g., as measured byvenous occlusion plethysmography) and typically is associated with amarkedly reduced forearm uptake of glucose. This can highlight theadverse effect of sympathetic activation on the ability of the cell totransport glucose across its membrane, a hallmark of insulin resistance.This can be the result of a reduced number of open capillaries due tovasoconstriction and/or an increase in the distance that insulin musttravel to reach the cell membrane from the intravascular compartment.Furthermore, this situation can be perpetuated if insulin resistancealready exists, which can reduce the ability of insulin to increasemuscle perfusion (e.g., by approximately 30%). The relevance of thesehemodynamic consequences of sympathetic activation is highlighted bystudies demonstrating a direct relationship between the sympatheticnerve firing rate to skeletal muscle tissue and insulin resistance andan inverse relationship between insulin resistance and the number ofopen capillaries.

Although hormone levels were not measured, it is striking that one ofthe two patients who was amenorrheic for the previous 3 years resumedirregular menses approximately 6 weeks after the renal neuromodulationprocedure. The findings discussed in this example suggest that alocalized, single intervention specifically targeting the renal nervesmay have beneficially influenced aspects of PCOS.

Example 2: Effect of Renal Neuromodulation on Hypertension

Patients were selected having a baseline systolic blood pressure of 160mm Hg or more (≥150 mm Hg for patients with type 2 diabetes) and takingthree or more antihypertensive drugs, and were randomly allocated intotwo groups: 51 assessed in a control group (antihypertensive drugs only)and 49 assessed in a treated group (undergone renal neuromodulation andantihypertensive drugs).

Patients in both groups were assessed at 6 months. Office-based bloodpressure measurements in the treated group were reduced by 32/12 mm Hg(SD 23/11, baseline of 178/96 mm Hg, p<0.0001), whereas they did notdiffer from baseline in the control group (change of 1/0 mm Hg, baselineof 178/97 mm Hg, p=0.77 systolic and p=0.83 diastolic). Between-groupdifferences in blood pressure at 6 months were 33/11 mm Hg (p<0.0001).At 6 months, 41 (84%) of 49 patients who underwent renal neuromodulationhad a reduction in systolic blood pressure of 10 mm Hg or more, comparedwith 18 (35%) of 51 control patients (p<0.0001).

VIII. FURTHER EXAMPLES

1. A method of treating a human patient diagnosed with polycystic ovarysyndrome, the method comprising:

-   -   intravascularly positioning a neuromodulation assembly within an        ovarian blood vessel of the patient and adjacent to an ovarian        nerve of the patient; and    -   reducing sympathetic neural activity in the patient by        delivering energy to the ovarian nerve via the neuromodulation        assembly to modulate the ovarian nerve,    -   wherein reducing sympathetic neural activity improves a        measurable physiological parameter corresponding to the        polycystic ovary syndrome of the patient.

2. The method of example 1 wherein reducing sympathetic neural activityin the patient in a manner that improves a measurable physiologicalparameter corresponding to the polycystic ovary syndrome comprisesreducing expansion of, maintaining the size of, or reducing the size ofan ovarian cyst in the patient.

3. The method of example 1 or example 2 wherein reducing sympatheticneural activity in the patient in a manner that improves a measurablephysiological parameter corresponding to the polycystic ovary syndromecomprises reducing the size of an ovarian cyst in the patient at leastabout 5% within about three months to about 12 months after reducingsympathetic neural activity in the patient by delivering energy to theovarian nerve.

4. The method of any one of examples 1-3 wherein reducing sympatheticneural activity in the patient in a manner that improves a measurablephysiological parameter corresponding to the polycystic ovary syndromecomprises reducing a number of ovarian cysts in the patient at leastabout 5% within about three months to about 12 months after reducingsympathetic neural activity in the patient by delivering energy to theovarian nerve.

5. The method of any one of examples 1-4 wherein reducing sympatheticneural activity in the patient in a manner that improves a measurablephysiological parameter corresponding to the polycystic ovary syndromecomprises reducing muscle sympathetic nerve activity in the patient.

6. The method of any one of examples 1-5 wherein reducing sympatheticneural activity in the patient in a manner that improves a measurablephysiological parameter corresponding to the polycystic ovary syndromecomprises reducing whole body norepinephrine spillover in the patient.

7. The method of any one of examples 1-6 wherein reducing sympatheticneural activity in the patient in a manner that improves a measurablephysiological parameter corresponding to the polycystic ovary syndromecomprises reducing ovarian norepinephrine spillover to plasma in thepatient.

8. The method of any one of examples 1-7 wherein the polycystic ovarysyndrome is associated with a condition including oligo/amenorrhea, andwherein reducing sympathetic neural activity in the patient in a mannerthat improves a measurable physiological parameter corresponding to thepolycystic ovary syndrome comprises causing resumption of menses in thepatient within about three months to about 12 months after reducingsympathetic neural activity in the patient by delivering energy to theovarian nerve.

9. The method of any one of examples 1-8 wherein reducing sympatheticneural activity in the patient by delivering energy to the ovarian nervecomprises at least partially inhibiting afferent neural activity.

10. The method of any one of examples 1-9 wherein reducing sympatheticneural activity in the patient by delivering energy to the ovarian nervecomprises at least partially inhibiting efferent neural activity.

11. The method of any one of examples 1-10 wherein reducing sympatheticneural activity in the patient by delivering energy to the ovarian nervecomprises modulating the ovarian nerve of the patient via anintravascularly positioned catheter carrying a neuromodulation assemblypositioned at least proximate to the ovarian nerve.

12. The method of any one of examples 1-11 wherein modulating theovarian nerve includes thermally modulating the ovarian nerve fromwithin the ovarian artery of the patient.

13. The method of example 12 wherein thermally modulating the ovariannerve includes cryotherapeutically cooling the ovarian nerve.

14. The method of example 12 or example 13 wherein thermally modulatingthe ovarian nerve includes delivering an energy field to the ovariannerve.

15. A method, comprising:

-   -   percutaneously introducing a neuromodulation assembly at a        distal portion of a treatment device proximate to neural fibers        innervating an ovary of a human patient diagnosed with        polycystic ovary syndrome or infertility;    -   partially disrupting function of the neural fibers innervating        the ovary by applying thermal energy to the neural fibers via        the neuromodulation assembly; and    -   removing the neuromodulation assembly from the patient after        treatment,    -   wherein partial disruption of the function of the neural fibers        innervating the ovary therapeutically treats the diagnosed        polycystic ovary syndrome or infertility.

16. The method of example 15 wherein the patient is diagnosed withpolycystic ovary syndrome, and wherein the method further comprisesimproving one or more physiological parameters corresponding to thepolycystic ovary syndrome.

17. The method of example 16 wherein improving one or more physiologicalparameters corresponding to the polycystic ovary syndrome includesreducing at least one of androgen levels, lipid levels, blood pressure,acne and hirsutism.

18. The method of any one of examples 15-17 wherein the patient isdiagnosed with infertility, and wherein partial disruption of thefunction of the neural fibers reverses infertility in the patient.

19. A method for treating polycystic ovary syndrome in a human patient,the method comprising:

-   -   positioning an energy delivery element of an ovarian denervation        catheter within an ovarian blood vessel of the patient and        adjacent to post-ganglionic neural fibers that innervate an        ovary of the patient; and    -   at least partially ablating the neural fibers innervating the        ovary of the patient via the energy delivery element,    -   wherein at least partially ablating the neural fibers        innervating the ovary results in a therapeutically beneficial        reduction in one or more physiological conditions associated        with polycystic ovary syndrome of the patient.

20. The method of example 19, further comprising administering one ormore pharmaceutical drugs to the patient, wherein the pharmaceuticaldrugs are selected from the group consisting of antihypertensive drugs,hormone therapy drugs and anti-diabetic drugs.

21. The method of example 19 or example 20 wherein the reduction in oneor more physiological conditions associated with polycystic ovarysyndrome includes a reduction in the number of ovarian cysts in thepatient.

IX. CONCLUSION

The above detailed descriptions of embodiments of the technology are notintended to be exhaustive or to limit the technology to the precise formdisclosed above. Although specific embodiments of, and examples for, thetechnology are described above for illustrative purposes, variousequivalent modifications are possible within the scope of thetechnology, as those skilled in the relevant art will recognize. Forexample, while steps are presented in a given order, alternativeembodiments may perform steps in a different order. For example, inadditional embodiments, the system 100 may include a treatment deviceconfigured to deliver therapeutic energy to the patient from an externallocation outside the patient's body, i.e., without direct or closecontact to the target site. The various embodiments described herein mayalso be combined to provide further embodiments.

From the foregoing, it will be appreciated that specific embodiments ofthe technology have been described herein for purposes of illustration,but well-known structures and functions have not been shown or describedin detail to avoid unnecessarily obscuring the description of theembodiments of the technology. Where the context permits, singular orplural terms may also include the plural or singular term, respectively.

Moreover, unless the word “or” is expressly limited to mean only asingle item exclusive from the other items in reference to a list of twoor more items, then the use of “or” in such a list is to be interpretedas including (a) any single item in the list, (b) all of the items inthe list, or (c) any combination of the items in the list. Additionally,the term “comprising” is used throughout to mean including at least therecited feature(s) such that any greater number of the same featureand/or additional types of other features are not precluded. It willalso be appreciated that specific embodiments have been described hereinfor purposes of illustration, but that various modifications may be madewithout deviating from the technology. Further, while advantagesassociated with certain embodiments of the technology have beendescribed in the context of those embodiments, other embodiments mayalso exhibit such advantages, and not all embodiments need necessarilyexhibit such advantages to fall within the scope of the technology.Accordingly, the disclosure and associated technology can encompassother embodiments not expressly shown or described herein.

I claim:
 1. A method, comprising: transluminally positioning an energy delivery element of a catheter within an ovarian blood vessel of a human patient diagnosed with polycystic ovary syndrome and adjacent to sympathetic neural fibers that innervate an ovary; and attenuating neural traffic along the sympathetic neural fibers via energy from the energy delivery element.
 2. The method of claim 1 further comprising comparing a baseline assessment of one or more physiological conditions associated with polycystic ovary syndrome and a post-treatment assessment of the one or more physiological conditions associated with the polycystic ovary syndrome of the human patient.
 3. The method of claim 2 wherein the one or more physiological conditions associated with the polycystic ovary syndrome includes oligomenorrhea or amenorrhea.
 4. The method of claim 3 wherein attenuating neural traffic along the sympathetic neural fibers results in resumption of menses in the human patient.
 5. The method of claim 2 wherein the one or more physiological conditions associated with the polycystic ovary syndrome includes an enlarged ovarian volume.
 6. The method of claim 2 wherein the one or more physiological conditions associated with the polycystic ovary syndrome includes androgenic hormone excess.
 7. The method of claim 1 wherein attenuating neural traffic along the sympathetic neural fibers results in at least one of a reduction in a number of ovarian cysts, a reduction in a size of an ovarian cyst, a reduction in an androgen level, a reduction in a severity of acne, a reduction in a severity of hirsutism, a reduction in lipid-levels, a reduction in blood pressure, a reduction in body weight, and a reduction in insulin resistance.
 8. The method of claim 1 wherein a result of attenuating neural traffic along the sympathetic neural fibers results is detectible within about 3 months to about 12 months following the treatment.
 9. The method of claim 1 wherein attenuating neural traffic along the sympathetic neural fibers via energy from the energy delivery element comprises thermally modulating the sympathetic neural fibers via a multi-electrode array from within the ovarian blood vessel of the human patient.
 10. A method, comprising: percutaneously introducing a neuromodulation assembly at a distal portion of a treatment device proximate to neural fibers innervating an ovary of a human patient diagnosed with polycystic ovary syndrome or ovulation-related infertility, wherein the neuromodulation assembly is introduced within an ovarian blood vessel of the human patient and; at least partially disrupting function of the neural fibers innervating the ovary by applying thermal energy to the neural fibers via the neuromodulation assembly being positioned adjacent to the neural fibers; and removing the neuromodulation assembly from the human patient after treatment; wherein at least partially disrupting the function of the neural fibers innervating the ovary therapeutically treats the diagnosed polycystic ovary syndrome or ovulation related infertility.
 11. The method of claim 10 wherein the human patient is diagnosed with polycystic ovary syndrome, and wherein the method further comprises reducing at least one of an average ovarian cyst size, a number of ovarian cysts, androgen levels, lipid levels, blood pressure, a severity of acne and a severity of hirsutism in the human patient.
 12. The method of claim 10 wherein the human patient is diagnosed with ovulation-related infertility, and wherein at least partially disrupting the function of the neural fibers innervating the ovary reverses the ovulation-related infertility in the human patient.
 13. The method of claim 10 wherein at least partially disrupting the function of the neural fibers innervating the ovary by applying thermal energy to the neural fibers via the neuromodulation assembly comprises delivering a thermal electric field to the neural fibers via at least one electrode positioned within an ovarian blood vessel of the human patient.
 14. A method, comprising: intravascularly positioning a neuromodulation assembly within an ovarian blood vessel and adjacent to an ovarian nerve of a female human patient diagnosed with dysfunctional hormone production; and reducing ovarian sympathetic neural activity in the female human patient by delivering energy to the ovarian nerve via the neuromodulation assembly and modulating the ovarian nerve.
 15. The method of claim 14 wherein the diagnosed dysfunctional hormone production in the female human patient includes an excess in androgen production, and wherein reducing the ovarian sympathetic neural activity reduces the androgen production in the female human patient.
 16. The method of claim 14 wherein the female human patient has an irregular endocrine hormone level, and wherein the endocrine hormone is selected from the group consisting of estrogen, follicle stimulating hormone, luteinizing hormone and testosterone.
 17. The method of claim 14 wherein reducing the ovarian sympathetic neural activity in the female human patient results in a beneficial improvement change in a measurable physiological parameter corresponding to the dysfunctional hormone production of the female human patient.
 18. The method of claim 17 wherein the change comprises at least one of reducing muscle sympathetic nerve activity, reducing whole body norepinephrine spillover to plasma and reducing ovarian norepinephrine spillover to plasma in the female human patient.
 19. The method of claim 14 wherein the female human patient is further diagnosed with oligoovulation or anovulation, and wherein reducing the ovarian sympathetic neural activity results in an increase in a number of instances of ovulation in the female human patient.
 20. The method of claim 14 wherein the female human patient is further diagnosed with polycystic ovary syndrome, and wherein reducing the ovarian sympathetic neural activity in the female human patient results in a change in a measurable physiological parameter corresponding to the polycystic ovary syndrome of the female human patient. 